The objectives of this research are to explore the pharmacology and toxicology of potential vasodilator drugs modeled after nitroprusside. Our previous discovery that nitroprusside can penetrate the intact human red cell and react with hemoglobin to generate methemoglobin and cyanmethemoglobin and to liberate free cyanide defined one toxic or even lethal effect of acute overdosage of nitroprusside. Since cyanide is metabolized in vivo to thiocyanate this discovery also defined the potential for chronic toxicity with nitroprusside administration over prolonged periods. Thiocyanate accumulation can lead to goiter or to central nervous system derangements. We are synthesizing a series of nitroso coordination complexes of ruthenium and testing them for their effects on blood pressure in comparison with nitroprusside and with nitrite. We are also attempting to define the fundamental toxic effects of rutheniumsalts and complexes. Some of these complexes will also be screened to see if they have antitumor activity. We are also exploring the toxicity of an aliphatic series of commercially important nitriles. These nitriles are toxic and teratogenic by virtue of cyanide release in vivo. We are examining the pathophysiologic basis for a unique hematologic effect of high altitude exposure, namely a hemoglobinemia in the face of a polycythemia. The molecular basis for the smooth muscle relaxing actions of nitroprusside with emphasis on cyclic nucleotide synthesis is also being examined.